G-protein signaling TC21 regulation pathway
TC21 regulation pathway
Related RAS viral (r-ras) oncogene homolog 2 ( TC21 ) belongs to Ras family ofsmall GTPases. It plays pivotal role in cell growth and differentiation [1],[2].
Guanine nucleotide exchange factors (GEFs), which promote GTP loading on TC21are essential for TC21 activation and GTPase activating proteins (GAPs), whichstimulate hydrolysis of GTP to GDP, negatively regulates TC21 activity [3]. Main GEFs for TC21 are RAS guanyl releasing proteins 1, 2 and 3 (CALDAG-GEFII, CALDAG-GEFI, CALDAG-GEFIII ) that can be activatedby increased Ca(2'+) cytosol and DAG levels [2], [4]; Ras protein-specific guanine nucleotide-releasing factor 1 ( RASGRF1 )that is activated by Lymphocyte-specific protein tyrosine kinase ( Lck )phosphorylation [5], [2], [6]; and Rap guaninenucleotide exchange factor (GEF) 1 ( C3G ) that is stimulated by Growth factorreceptor-bound protein 2 ( GRB2 ) binding [7], [2].
Known GEF for TC21 is RAS p21 protein activator 1 ( p120GAP ) [8], [2]. Breakpoint cluster region ( BCR ) via Docking protein1 and 2 ( DOK1, DOK2 ) phosphorylation stimulates GAP activity ofp120GAP [9], [3]. V-src sarcoma ( c-Src )phosphorylation and RAP1A, member of RAS oncogene family ( RAP-1A ) bindingsuppress GAP activity of p120GAP [10], [6]. RAS p21protein activator 2 ( RASA2 ), activated by Inositol 1,3,4,5-tetrakisphosphatecytosol binding or G-protein alpha-12 family signaling, also exhibits GAPactivity towards TC21 [11], [12], [2]. Anotherknown TC21 GAP is Neurofibromin 1 ( Neurofibromin ) [2],[13].
GTP-bound TC21 can stimulate the Raf kinase family members v-raf-1 murineleukemia viral oncogene homolog 1 ( c-Raf-1) and v-raf murine sarcoma viraloncogene homolog B1 (B-raf) and thus promote activation of Mitogen-activatedprotein kinases 1 and 3 ( Erk(MAPK1/3) ) [14], [15].
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